Karolinska Institutet, Department of Medical Biochemistry and Biophysics, Division of Chemistry 2 , Scheeles väg 2, Stockholm, S-171 77 , Sweden
Expert Opin Ther Targets. 2014 Jan;18(1):79-93. doi: 10.1517/14728222.2013.843671. Epub 2013 Oct 4.
Leukotriene (LT) B(4) is a powerful proinflammatory lipid mediator and triggers adherence to the endothelium, activates and recruits leukocytes to the site of injury. When formed in excess, LTB(4) plays a pathogenic role and may sustain chronic inflammation in diseases such as asthma, rheumatoid arthritis, and inflammatory bowel disease. Recent investigations have also indicated that LTB(4) is involved in cardiovascular diseases.
As the 5-lipoxygenase pathway involves several discrete, tightly coupled, enzymes, which convert the substrate, 'step by step', into bioactive products, several different strategies have been used to target LTB(4) as a means to treat inflammation. Here, we discuss recent findings regarding the development of selective enzyme inhibitors and antagonists for LTB(4) receptors, as well as their application in preclinical and clinical studies.
Components of the 5-lipoxygenase pathway have received considerable attention as candidate drug targets resulting in one new class of medications against asthma, that is, the antileukotrienes. However, efforts to specifically target LTB(4) have not yet been fruitful in the clinical setting, in spite of very promising preclinical data. Recently, crystal structures along with hitherto unknown functions of key enzymes in the leukotriene cascade have emerged, offering new opportunities for drug development and, with time, pharmacological intervention in LTB(4)-mediated pathologies.
白三烯（LT）B（4）是一种强大的促炎脂质介质，可触发与内皮细胞的黏附，激活并募集白细胞到损伤部位。当过量形成时，LTB（4）发挥致病作用，并可能在哮喘、类风湿关节炎和炎症性肠病等疾病中维持慢性炎症。最近的研究还表明，LTB（4）与心血管疾病有关。
由于 5-脂氧合酶途径涉及几个离散的、紧密偶联的酶，它们将底物“一步一步”转化为生物活性产物，因此已经使用了几种不同的策略来靶向 LTB（4）作为治疗炎症的手段。在这里，我们讨论了最近关于开发 LTB（4）受体的选择性酶抑制剂和拮抗剂的发现，以及它们在临床前和临床研究中的应用。
5-脂氧合酶途径的成分作为候选药物靶点受到了极大的关注，这导致了一类新的哮喘治疗药物，即抗白三烯。然而，尽管有非常有希望的临床前数据，但专门针对 LTB（4）的努力在临床环境中尚未取得成功。最近，随着白三烯级联中的关键酶的晶体结构以及迄今为止未知的功能的出现，为药物开发提供了新的机会，并随着时间的推移，为 LTB（4）介导的病理提供了药理干预的机会。
